EP0479546A2 - Piperazine derivatives - Google Patents

Piperazine derivatives Download PDF

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Publication number
EP0479546A2
EP0479546A2 EP91308969A EP91308969A EP0479546A2 EP 0479546 A2 EP0479546 A2 EP 0479546A2 EP 91308969 A EP91308969 A EP 91308969A EP 91308969 A EP91308969 A EP 91308969A EP 0479546 A2 EP0479546 A2 EP 0479546A2
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Prior art keywords
compound
methoxyphenyl
piperazine
formula
phenyl
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German (de)
French (fr)
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EP0479546A3 (en
EP0479546B1 (en
Inventor
Terence James Ward
Graham John Warrellow
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John Wyeth and Brother Ltd
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John Wyeth and Brother Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/20Hypnotics; Sedatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/22Anxiolytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/26Psychostimulants, e.g. nicotine, cocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D271/00Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/061,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings

Definitions

  • This invention relates to piperazine derivatives, to processes for their preparation, to their use and to pharmaceutical compositions containing them.
  • the novel compounds act upon the central nervous system by binding to 5-HT receptors (as more fully explained below) and hence can be used as medicaments for treating human and other mammals.
  • novel compounds of the invention are those of the general formula and the pharmaceutically acceptable acid addition salts thereof.
  • lower as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms.
  • loweralkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and isopentyl.
  • aryl means an aromatic radical having 6 to 12 carbon atoms (e.g. phenyl or naphthyl) which optionally may be substituted by one or more substituents.
  • R 1 when R 1 is aryl it may be a phenyl or naphthyl radical optionally substituted by one or more lower alkyl, lower alkoxy (e.g. methoxy, ethoxy, n or i-propoxy, butoxy, cyclopropylmethoxy), halogen, halo(lower)alkyl (e.g.
  • R 4 is aryl it may be, for example, a phenyl or naphthyl radical optionally substituted by one or more of the substituents listed above and/or by one or more hydroxy, hydroxy(lower)alkyl (e.g. hydroxymethyl), -CONR 5 R 6 (where R 5 and R 6 are each hydrogen or lower alkyl) or -NHS0 2 (lower)alkyl substituents.
  • the aryl radical R 4 contains a substituent (e.g. lower alkoxy) in the ortho position.
  • R 4 is o-(lower)alkoxyphenyl (e.g. o-methoxyphenyl).
  • heteroaryl refers to an aromatic radical containing one or more hetero ring atoms (e.g. oxygen, nitrogen, sulphur) and which may be optionally substituted by one or more substituents.
  • Preferred examples of substituents for the heteroaryl radical R 1 are given above for the aryl radical R 1 while preferred examples of substituents for the heteroaryl radical R 4 are given above for the aryl radical R 4 .
  • the heteroaryl radical may be, for example, mono- or bicyclic containing up to 11 ring atoms.
  • the heteroaryl radical may, for example be a monocyclic radical containing 5 to 7 ring atoms or a bicyclic radical containing 9 to 11 ring atoms.
  • the hetero ring contains a nitrogen hetero atom with or without further hetero atoms.
  • the heteroaryl group R 1 are optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, benzimidazolyl and oxadiazolyl tetrazolyl and oxadiazolyl. These groups may be connected to the remainder of the molecule via a ring heteroatom or a ring C atom.
  • the heteroaryl group R 4 include optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl and isoquinolinyl.
  • R 2 is a mono- or bicyclic heterocyclic radical.
  • the radical may be heteroaryl radical such as those mentioned above including the preferred examples given in connection with radical R 1 .
  • R 2 may be fully or partially saturated mono- or bicyclic heterocyclic ring.
  • the mono or bicyclic ring contains one or more hetero ring atoms (e.g. oxygen, nitrogen and/or sulphur) and may be optionally substituted by one or more substituents (such as those given above for the group R l ).
  • the mono or bicyclic ring preferably contains up to 10 carbon atoms. Examples include optionally substituted imidazolinyl, oxazolinyl, pyrrolidinyl, piperidinyl, morpholinyl and azepinyl.
  • radical -A- examples include -CH 2 - -CHCH 3 -, -C(CH 3 ) 2 -, -CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-, - CH(CH 3 ).CH(CH 3 )- and -CH 2 -C(CH 3 ) 2 -.
  • Preferred compounds have the following substituents either independently or in combination:-(a) A is CH 2
  • the compounds of the invention may be prepared by methods known in the art from known starting materials or starting materials that may be prepared by conventional methods.
  • One method of preparing the compounds of the invention comprises alkylating a piperazine derivative of formula with an alkylating agent providing the group
  • the alkylating agent may be, for example, a compound of formula where R 1 , R 2 , R 3 and A are as defined above and X is a leaving group such as halogen or an alkyl- or aryl-sulphonyloxy group.
  • the alkylating agent may be an unsaturated compound of formula (where at least one of the groups R 1 and R 2 is an electron withdrawing group e.g. an optionally substituted 2-or 4- pyridyl, 2- or 4- pyrimidyl or 2- pyrazinyl group) and the compound of formula (V) is reacted with the piperazine compound of formula (II) by means of a Michael reaction.
  • the compounds of formula (I) may also be prepared by reduction of an amide of formula where R, R l , R 2 , R 3 and R 4 are as defined above and A 1 is methylene optionally substituted by one or two (lower)alkyl groups.
  • the reduction may, for example, be carried out with a hydride transfer agent e.g. borane- dimethylsulphide or lithium aluminium hydride.
  • the starting amide of formula (VI) may be made by acylating a piperazine derivative of formula (II) above with an acylating derivative of an acid of formula
  • the acylating derivative may be, for example, the acid chloride.
  • R 1 or R 2 is a heterocyclic radical attached via a ring N-atom
  • R 1 or R 2 is a heterocyclic radical attached via a ring N-atom
  • R l H or R 2 H e.g. imidazole
  • R, R 1 , R 2 , R 3 , R 4 and A are as defined above
  • Y is a leaving group such as halogen or an alkyl- or aryl- sulphonyloxy group.
  • An alternative method of preparing the compounds of the invention comprises arylating or heteroarylating a compound of formula
  • the compound of formula (IX) may be reacted with a fluorobenzene compound which is substituted by an electron withdrawing group (e.g. -CHO, cyano, nitro).
  • an electron withdrawing group e.g. -CHO, cyano, nitro
  • Another method of preparing the compounds of the invention comprises reacting a compound having the anion with a compound of formula where X is a leaving group which is activated towards nucleophilic displacement.
  • R 2 can be an electron withdrawing radical (e.g. an optionally substituted 2- or 4- pyridyl, 2- or 4- pyrimidyl or 2- pyrazinyl group) and X a leaving group such as fluorine.
  • the radical R 1 is also, preferably an electron withdrawing group.
  • the anion (X) may be prepared by reacting the compound R R 1 CH 2 A-N N-R 4 (XII) with a base e.g. n-butyl lithium.
  • Compounds of the invention may also be prepared by forming an anion of a compound of formula (e.g. with a strong base) and reacting with a compound of formula where A, R, R 1 , R 2 , R 3 and R 4 are as defined above and Y is a leaving group such as halogen or an alkyl- or aryl-sulphonyloxy group.
  • R 2' may be an alkoxycarbonyl group which may be cyclised by reaction an amidoxime (eg acetamidoxime) to give a compound in which R 2 is a 1,2,4-oxidiazol-5-yl radical.
  • a substituent on the group R 4 or on the group R 1 and/or R 2 is other than the one required the substituent may be converted to the desired substituent by known methods.
  • a -CHO substituent may be reduced to hydroxymethyl
  • a nitro group may be reduced to a amino group which may be sulphonated to give a -NHS0 2 (lower)alkyl substituent
  • a cyano group may be hydrolysed to an acid which may be esterified or converted to an amide.
  • R 1 and R 2 may be converted into another heterocyclic group by methods known per se.
  • the processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic, p-toluenesulphonic, oxalic and succinic acids.
  • the compounds of the invention may contain an asymmetric carbon atom, so that the compounds can exist in different steroisomeric forms.
  • the compounds can be for example, racemates or optically active forms.
  • the optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
  • the compounds of the present invention possess pharmacological activity. In particular, they act on the central nervous system by binding to 5-HT receptors. In pharmacological testing it has been shown that the compounds particularly bind to receptors of the 5-HT 1A type. In general, the compounds selectively bind to receptors of the 5-HT 1A type. Many exhibit activity as 5-HT 1A antagonists in pharmacological testing.
  • the pharmacological testing of the compounds indicates that they can be used for the treatment of neuro-psychiatric disorders, such as anxiety and depression in mammals, particularly humans. They may also be useful as hypotensives and as agents for regulating the sleep/wake cycle, feeding behaviour and/or sexual function.
  • the compounds of the invention are tested for 5-HT 1A receptor binding activity in rat hippocampal membrane homogenate by the method of B S Alexander and M D Wood, J Pharm Pharmacol, 1988, 40, 888-891.
  • the compounds are tested for 5-HT 1A receptor antagonism activity in a test involving the antagonism of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH DPAT) syndrome in the rat.
  • (R,S)-1-(2-Methoxyphenyl)-4-[2-(IH- imidazol-1-yl)-2-(phenyl)ethylpiperazine had MED of 1 mg/kg subcut and 10 mg/kg p.o when tested in this procedure.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier Any suitable carrier known in the art can be used to prepare the pharmaceutical composition.
  • the carrier is generally a solid or liquid or a mixture of a solid or liquid.
  • Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatine capsules), suppositories and pessaries.
  • a solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99%, e.g.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • composition is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.
  • Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions.
  • the active ingredient for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweetners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers orosmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution, alcohols, e.g. glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid composition form.
  • the pharmaceutical composition is in unit dosage form e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged composition, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquid.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compostions in package form.
  • the quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient.
  • the above pure isomer (3.55g, 0.0114 m) was mixed in dichloromethane (100 ml) with triphenylphosphine (3.59 g, 0.014 m) and imidazole (9 g, 0.132 m). The solution was treated over 8 minutes with diethylazodicarboxylate (2.6 ml) in dichloromethane. The solution was stirred at ambient temperature for 3 days and then evaporated.
  • the above pure isomer (5.15 g, 0.0165m) was mixed in dichloromethane (100 ml) with triphenylphosphine (5.21 g, 0.02m) and imidazole (13 g, 0.2 m).
  • the solution was treated over 10mins with diethylazodicarboxylate (3.8 ml) in dichloromethane (5 ml).
  • the solution was stirred 3 days at ambient temperature and then evaporated.
  • the residue was dissolved in ether (200 ml) and washed with water.
  • the ether layer was then shaken with 6N HCI (3x100 ml).
  • the combined HCI layers were shaken with ether.
  • the base was dissolved in ethanol (5 ml), acidified with ethanolic-HBr and diluted with ether (3 ml) to precipitate the title compound as the trihydrobromide 0.46 g, m.p. 224-226°C.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
  • Hydrogenated Pyridines (AREA)
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Abstract

Compounds of formula
Figure imga0001
where A is an alkylene chain of 1 or 2 carbon atoms optionally substituted by one or more lower alkyl groups,
  • R is hydrogen or lower alkyl,
  • R1 is an aryl or heteroaryl radical,
  • R2 is a mono- or bicyclic heterocyclic radical,
  • R3 is hydrogen, lower alkyl or hydroxy and
  • R4 is a aryl or heteroaryl radical,

and their pharmaceutically acceptable acid addition salts are 5-HT1A binding agents which may be used, for example, for the treatment of CNS - disorders such as anxiety.

Description

  • This invention relates to piperazine derivatives, to processes for their preparation, to their use and to pharmaceutical compositions containing them. The novel compounds act upon the central nervous system by binding to 5-HT receptors (as more fully explained below) and hence can be used as medicaments for treating human and other mammals.
  • The novel compounds of the invention are those of the general formula
    Figure imgb0001
    and the pharmaceutically acceptable acid addition salts thereof.
  • In formula (I):
    • A is an alkylene chain of 1 or 2 carbon atoms optionally substituted by one or more lower alkyl groups,
    • R is hydrogen or lower alkyl,
    • R1 is an aryl or heteroaryl radical,
    • R2 is a mono- or bicyclic heterocyclic radical,
    • R3 is hydrogen or lower alkyl and
    • R4 is a aryl or heteroaryl radical.
  • The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of "loweralkyl" radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and isopentyl.
  • When used herein "aryl" means an aromatic radical having 6 to 12 carbon atoms (e.g. phenyl or naphthyl) which optionally may be substituted by one or more substituents. For example, when R1 is aryl it may be a phenyl or naphthyl radical optionally substituted by one or more lower alkyl, lower alkoxy (e.g. methoxy, ethoxy, n or i-propoxy, butoxy, cyclopropylmethoxy), halogen, halo(lower)alkyl (e.g. trifluoromethyl), nitro, amino, (lower)alkylamino, di(lower)alkylamino, phenyl, halophenyl, (lower)alkylphenyl or (lower)alkoxyphenyl substituents. When R4 is aryl it may be, for example, a phenyl or naphthyl radical optionally substituted by one or more of the substituents listed above and/or by one or more hydroxy, hydroxy(lower)alkyl (e.g. hydroxymethyl), -CONR5R6 (where R5 and R6 are each hydrogen or lower alkyl) or -NHS02(lower)alkyl substituents. Preferably the aryl radical R4 contains a substituent (e.g. lower alkoxy) in the ortho position. A particularly preferred example of R4 is o-(lower)alkoxyphenyl (e.g. o-methoxyphenyl).
  • The term 'heteroaryl' refers to an aromatic radical containing one or more hetero ring atoms (e.g. oxygen, nitrogen, sulphur) and which may be optionally substituted by one or more substituents. Preferred examples of substituents for the heteroaryl radical R1 are given above for the aryl radical R1 while preferred examples of substituents for the heteroaryl radical R4 are given above for the aryl radical R4. The heteroaryl radical may be, for example, mono- or bicyclic containing up to 11 ring atoms. The heteroaryl radical may, for example be a monocyclic radical containing 5 to 7 ring atoms or a bicyclic radical containing 9 to 11 ring atoms. Preferably the hetero ring contains a nitrogen hetero atom with or without further hetero atoms. Examples of the heteroaryl group R1 are optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, benzimidazolyl and oxadiazolyl tetrazolyl and oxadiazolyl. These groups may be connected to the remainder of the molecule via a ring heteroatom or a ring C atom. Examples of the heteroaryl group R4 include optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl and isoquinolinyl.
  • R2 is a mono- or bicyclic heterocyclic radical. The radical may be heteroaryl radical such as those mentioned above including the preferred examples given in connection with radical R1. In addition R2 may be fully or partially saturated mono- or bicyclic heterocyclic ring. The mono or bicyclic ring contains one or more hetero ring atoms (e.g. oxygen, nitrogen and/or sulphur) and may be optionally substituted by one or more substituents (such as those given above for the group Rl). The mono or bicyclic ring preferably contains up to 10 carbon atoms. Examples include optionally substituted imidazolinyl, oxazolinyl, pyrrolidinyl, piperidinyl, morpholinyl and azepinyl.
  • Examples of the radical -A- include -CH2- -CHCH3-, -C(CH3)2-, -CH2-CH2-, -CH2-CH(CH3)-, - CH(CH3).CH(CH3)- and -CH2-C(CH3)2-.
  • Preferred compounds have the following substituents either independently or in combination:-(a) A is CH2
    • (b) R1 is aryl, preferably phenyl
    • (c) R2 is 1H imidazol-1-yl
    • (d) R3 is hydrogen
    • (e) R4 is aryl
    • (f) R is hydrogen
  • The compounds of the invention may be prepared by methods known in the art from known starting materials or starting materials that may be prepared by conventional methods.
  • One method of preparing the compounds of the invention comprises alkylating a piperazine derivative of formula
    Figure imgb0002
    with an alkylating agent providing the group
    Figure imgb0003
  • The alkylating agent may be, for example, a compound of formula
    Figure imgb0004
    where R1, R2, R3 and A are as defined above and X is a leaving group such as halogen or an alkyl- or aryl-sulphonyloxy group. Alternatively the alkylating agent may be an unsaturated compound of formula
    Figure imgb0005
    (where at least one of the groups R1 and R2 is an electron withdrawing group e.g. an optionally substituted 2-or 4- pyridyl, 2- or 4- pyrimidyl or 2- pyrazinyl group) and the compound of formula (V) is reacted with the piperazine compound of formula (II) by means of a Michael reaction.
  • The compounds of formula (I) may also be prepared by reduction of an amide of formula
    Figure imgb0006
    where R, Rl, R2, R3 and R4 are as defined above and A1 is methylene optionally substituted by one or two (lower)alkyl groups. The reduction may, for example, be carried out with a hydride transfer agent e.g. borane- dimethylsulphide or lithium aluminium hydride. The starting amide of formula (VI) may be made by acylating a piperazine derivative of formula (II) above with an acylating derivative of an acid of formula
    Figure imgb0007
  • The acylating derivative may be, for example, the acid chloride.
  • Compounds of the invention in which R1 or R2 is a heterocyclic radical attached via a ring N-atom may be prepared by reacting a heterocyclic compound of formula RlH or R2H e.g. imidazole with, respectively a compound of formula
    Figure imgb0008
    or
    Figure imgb0009
    where R, R1, R2, R3, R4 and A are as defined above, and Y is a leaving group such as halogen or an alkyl- or aryl- sulphonyloxy group.
  • An alternative method of preparing the compounds of the invention comprises arylating or heteroarylating a compound of formula
    Figure imgb0010
  • For example the compound of formula (IX) may be reacted with a fluorobenzene compound which is substituted by an electron withdrawing group (e.g. -CHO, cyano, nitro).
  • Another method of preparing the compounds of the invention comprises reacting a compound having the anion
    Figure imgb0011
    with a compound of formula
    Figure imgb0012
    where X is a leaving group which is activated towards nucleophilic displacement. For example R2 can be an electron withdrawing radical (e.g. an optionally substituted 2- or 4- pyridyl, 2- or 4- pyrimidyl or 2- pyrazinyl group) and X a leaving group such as fluorine. The radical R1 is also, preferably an electron withdrawing group. The anion (X) may be prepared by reacting the compound R R1 CH2 A-N N-R 4 (XII) with a base e.g. n-butyl lithium.
  • Compounds of the invention may also be prepared by forming an anion of a compound of formula
    Figure imgb0013
    (e.g. with a strong base) and reacting with a compound of formula
    Figure imgb0014
    where A, R, R1, R2, R3 and R4 are as defined above and Y is a leaving group such as halogen or an alkyl- or aryl-sulphonyloxy group.
  • In a further method of preparing the compounds of the invention a compound of formula
    Figure imgb0015
    in which R, R1, R3, R4 and A are as defined above and RZ' is an uncyclised group which is a precursor of a mono or bicyclic heterocyclic radical is cyclised to the compound of the invention. The cyclisation may be carried out by methods known per se. For example R2' may be an alkoxycarbonyl group which may be cyclised by reaction an amidoxime (eg acetamidoxime) to give a compound in which R2 is a 1,2,4-oxidiazol-5-yl radical.
  • If in any of the other processes mentioned herein, a substituent on the group R4 or on the group R1 and/or R2 is other than the one required the substituent may be converted to the desired substituent by known methods. For example, a -CHO substituent may be reduced to hydroxymethyl, a nitro group may be reduced to a amino group which may be sulphonated to give a -NHS02(lower)alkyl substituent, a cyano group may be hydrolysed to an acid which may be esterified or converted to an amide. Furthermore one heterocyclic group, R1 and R2 may be converted into another heterocyclic group by methods known per se.
  • The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic, p-toluenesulphonic, oxalic and succinic acids.
  • The compounds of the invention may contain an asymmetric carbon atom, so that the compounds can exist in different steroisomeric forms. The compounds can be for example, racemates or optically active forms. The optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
  • The compounds of the present invention possess pharmacological activity. In particular, they act on the central nervous system by binding to 5-HT receptors. In pharmacological testing it has been shown that the compounds particularly bind to receptors of the 5-HT1A type. In general, the compounds selectively bind to receptors of the 5-HT1A type. Many exhibit activity as 5-HT 1A antagonists in pharmacological testing. The pharmacological testing of the compounds indicates that they can be used for the treatment of neuro-psychiatric disorders, such as anxiety and depression in mammals, particularly humans. They may also be useful as hypotensives and as agents for regulating the sleep/wake cycle, feeding behaviour and/or sexual function.
  • The compounds of the invention are tested for 5-HT1A receptor binding activity in rat hippocampal membrane homogenate by the method of B S Alexander and M D Wood, J Pharm Pharmacol, 1988, 40, 888-891. (R,S)-1-(2-Methoxyphenyl)-4-[2-(IH-imidazol-1-yl)-2 (phenyl) ethyl]piperazine, a representative compound of the invention had an IC50 of 15.8nM in this procedure.
  • The compounds are tested for 5-HT1A receptor antagonism activity in a test involving the antagonism of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH DPAT) syndrome in the rat. (R,S)-1-(2-Methoxyphenyl)-4-[2-(IH- imidazol-1-yl)-2-(phenyl)ethylpiperazine had MED of 1 mg/kg subcut and 10 mg/kg p.o when tested in this procedure.
  • The invention also provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid or a mixture of a solid or liquid.
  • Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatine capsules), suppositories and pessaries. A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, e.g. from 0.03 to 99%. preferably 1 to 80% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.
  • Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions. The active ingredient, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweetners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers orosmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution, alcohols, e.g. glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid composition form.
  • Preferably the pharmaceutical composition is in unit dosage form e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged composition, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquid. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compostions in package form. The quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient.
  • The following Examples illustrate the invention:
  • Example 1 1-(2-Methoxyphenyl)-4-[2-1 H-imidazol-1-yl)-2-(phenyl)ethyl]piperazine (a) 1-(2-Hydroxy-2-phenylethyl)-4-(2-methoxyphenyl)piperazine
  • 1-(o-Methoxyphenyl)piperazine (25g) in acetonitrile (250 ml) was added dropwise to a solution of styrene oxide (14.92 ml) in acetonitrile (150 ml) at room temperature. The reaction mixture was stirred overnight, refluxed for 28 hours and allowed to stand overnight. The solvent was removed and the residue dissolved in ether and washed with water. The ether layer was evaporated to give the crude title compound (ca 40 g).
  • (b) 1-(2-Methoxyphenyl)-4-[2-(1 H-imidazol-1-yl)-2-(phenyl)ethyl]piperazine
  • A mixture of 1-(2-hydroxy-2-phenylethyl) -4-(2-methoxyphenyl)piperazine hydrochloride (1.6 g) and thionyl chloride (5 ml) was stirred at reflux for 5 min. The clear solution was then diluted with ether and the precipitated product collected by filtration and washed well with ether. The solid was added to a solution of imidazole (2.4 g, 40 mmol) in methanol (20 ml) and heated to reflux for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed several times with water, dried (Na2SO4), and concentrated in vacuo. The residue was dissolved in ethanol (10 ml) and acidified with ethereal-HC1. Further addition of ether precipitated the hydrochloride (1.07 g, 55%), which was recrystallised from methanol-ethanol (20 ml; 1:3) to afford the title compound as the trihydrochloride 1.25 hydrate (0.54 g), m.p. 203-204°C (Found: C,53.2; H,6.4; N,11.2. C22H26N40.3HC1.1.25H20 requires C,53.4; H,6.4; N,11.3%).
  • Example 2 1-(2-Methoxyphenyl)-4-[2-(2-Methyl-[1 H]imidazol-1-yl)-2-phenyl)ethyl]piperazine
  • To a mixture of 1-(2-hydroxy-2-phenylethyl)-4-(2-methoxyphenyl)-piperazine (5.67 g; 0.02 m); triphenylphosphine (5.69 g; 0.0217 m) and 2-methylimidazole (16 g; 0.195m) in dichloromethane (150 ml) was added diethylazodicarboxylate (3.82 ml; 0.024 m) in dichloromethane (10 ml) over 10 minutes at ambient temperature. After the initial exotherm subsided, the mixture was stirred for 3 days. The residue on evaporation was treated with 3N HCI. Ether was added and the resulting two layers separated. The ether layer was washed twice with 3N HCI. The combined HCI layers were basified with ammonia and then shaken with ether (3 portions). The ether layers were washed well with water. The final ether layer was dried over magnesium sulfate. The oil on evaporation was dissolved in hot ethanol and acidified with ethanolic HCI. The solvent was evaporated to leave a foam that solidified when triturated with ether. A little ethanol was added and the solid filtered off. The mother liquor yielded 0.67 g of product which was recrystallised from ethanol to give the title compound as the trihydrochloride, m.p. >177°C. Found: C,54.45; H,6.69; N,10.92%. C23H28N40.3HCl.H20 requires C,54.82; H,6.6; N,11.12%.
  • Example 3 1-(2-Methoxyphenyl)-4-[2-(1-pyrrolidinyl)-2-(phenyl)ethyl]piperazine
  • A mixture of 1-(2-hydroxy-2-phenylethyl)-4-(2-methoxyphenyl)-piperazine (5.65 g; 0.018 m), triphenylphosphine (5.69 g, 0.022m) and pyrollidine (15 ml; 0.18 m) in dichloromethane (100 ml) was stirred at 0.5°C and a solution of diethylazodicarboxylate (3.8 ml, 0.024 m) in dichloromethane (5 ml) was added over 5 minutes. The resulting yellow solution was stirred at ambient temperature for 48 hrs. The residue on evaporation was partitioned between ether and 3N aq. hydrochloric acid. The combined HCl layers were washed with ether and then basified with ammonia and shaken with 3 portions of ether. The ether layers were washed well with water and dried over magnesium sulfate to give an oil which was chromatographed to give 0.96 g of the title compound. The crude oil in ethanol was acidified with ethanolic hydrogen chloride. The solvent was evaporated, and the residual foam solidified when triturated with ethanol and ether. The solid was recrystallised from ethanol to give the title compound as the dihydrochloride (0.45 g), m.p. 214-18°C(d).
  • Example 4 1-(2-Methoxyphenyl)-4-[2-(1H-imidazol-1-yl)-2-(4-fluorophenyl)ethyl]piperazine
  • Thionyl chloride (1.25 g, 0.82 ml) was added dropwise to a stirred solution of 1-[2-hydroxy-2-(4-fluorophenyl]-4-(2-methoxyphenyl)-piperazine (2.31 g, 7 mmol) in DMF (15 ml) maintained below 15°C by ice-cooling. The solution was allowed to stand at ambient temperature for 0.5 h and imidazole (4.76 g, 70 mmol) added. The mixture was heated at 80°C for 1.5 h, then cooled, diluted with water and extracted into ethyl acetate. The extract was washed with water, dried over Na2S04 and evaporated. The residue was dissolved in ethanol (15 ml) and acidified with ethereal-HCI to precipitate the title compound as the hydrochloride (1.58 g), m.p. 242-243°C.
  • Example 5 (a) 1-(2-Methoxyphenyl)-4-[2-phenyl-2-(1H-benzimidazol-1-yl)-1-oxoethyl]piperazine
  • A mixture of sodium hydride (0.47 g of 80% dispersion) in dry dimethyl formamide (10 ml) at 0-5°C was treated with benzimidazole (1.584 g) and the mixture stirred for 30 mins. A solution of 1-(2-methoxyphenyl)-4-(2-chloro-1-oxo-2-phenylethyl)piperazine (4.624 g) in dry DMF (20 ml) was added and the mixture was stirred at 90°C for 5 hrs then at ambient temperature overnight. The suspension was filtered and the solvent evaporated under vacuum. The residue, in dichloromethane was washed well with water and dried over magnesium sulphate, to give 6 g of an oil. The crude product was purified by dry column flash chromatography to give the title compound (2.4 g).
  • (b) 1-(2-methoxyphenyl)-4-[2-(1 H-benzimidazol-1-yl)-2-phenylethyl]piperazine.
  • 1-(2-methoxyphenyl)-4-[2-phenyl-2-(1 H-benzimidazol-1-yl)-1-oxoethyl]piperazine (9.4 g) in 50 ml dry tetrahydrofuran was treated with borane - dimethylsulphide in THF (100mi of 2.0 M solution) over 30 mins and then heated to reflux. After 3 hrs at reflux following by overnight stirring at ambient temperature the mixture was cooled to 0-5°C. Concentrated hydrochloric acid (50 ml) was added over 30 mins and the mix was stirred at 90°C for 12 hrs, then at ambient temperature for 4 hrs. The mixture was filtered and the filtrate was evaporated, the residue partitioned between water and diethylether and the aqueous layer extracted with ether. The ether layers were washed with water and evaporated to give a solid that recrystallised from cyclohexane to give title compound (3.85 g) which was converted to its hydrochloride, m.p. 196-201°C.
  • Example 6 1-(2-Methoxyphenyl)-4-[2-phenyl-2-(4-phenyl-1 H-imidazol-1-yl)ethyl]piperazine
  • 2.0 M Borane-methylsulphide in THF (45 ml) was added over 45 mins to a solution of 1-(2-methoxyphenyl)-4-[1-oxo-2-phenyl-2-(4-phenyl-1H-imidazol-1-yl)ethyl]piperazine (4.0 g, 0.009 m, prepared in an analogous manner to the method of Example 5a) in dry THF (30 ml) at ambient temperature, and the mixture was then refluxed 24 hrs. The cooled mixture was treated with conc. HCI (25 ml) dropwise over 30 mins and the resulting white suspension was then heated at 90°C for 4 hrs. After further standing 48 hrs the mixture was filtered. The white solid was washed with 6N HCI and dried, then recrystallised from ethanol to yield the title compound as the trihydrochloride (1.425 g), m.p. 233-36°C(d).
  • Example 7 (R)-[1-(2-Methoxyphenyl)-4-(2-phenyl-2-hydroxyethyl)piperazine]
  • 2-Methoxyphenylpiperazine (19.84 g, 0.103 m) in dry acetonitrile (150 ml) was refluxed with (R)-styrene oxide (12.4 g, 0.104 m). The residue on evaporation was chromatographed on silica using ethyl acetate as eluant to give two main fractions. The first fraction (4.3 g) contained some styrene oxide, which was removed by acid-base extraction to give 3.55 g of pure title compound. The second fraction (9.5 g) was 95% title compound and approximately 5% of the regioisomer.
  • (S)-[1-(2-Methoxyphenyl)-4-(2-(1 H-imidazol-1-yl)-2-phenylethyl)piperazine].
  • The above pure isomer (3.55g, 0.0114 m) was mixed in dichloromethane (100 ml) with triphenylphosphine (3.59 g, 0.014 m) and imidazole (9 g, 0.132 m). The solution was treated over 8 minutes with diethylazodicarboxylate (2.6 ml) in dichloromethane. The solution was stirred at ambient temperature for 3 days and then evaporated.
  • The residue was dissolved in diethylether (150 ml) and washed with water. The ether layer was then shaken with 6N HCI (3x100 ml). The combined HCI layers were washed with ether. The HCI layers were cooled and basified with 0.880 ammonia, and shaken with ether (3x100 ml). The ether extracts were washed with water and dried over magnesium sulphate, to give 6.7 g of an oil. The oil was dissolved in ethanol (150 ml) at 70°C and acidified in ethanolic HCI. The solid which precipitated on cooling was filtered off to give the trihydrochloride monohydrate, m.p. 193-197°C, [a]p-27°.
  • Example 8 (S)-[1-(2-Methoxyphenyl)-4-(2-phenyl-2-hydroxyethyl)piperazine]
  • 2-Methoxyphenylpiperazine (17.4 g, 0.0906 m) in dry acetonitrile (150 ml) was refluxed 24 hrs with (S)-styrene oxide (10.84 g, 0.09 m). The residue on evaporation was treated by acid-base extraction to remove unreacted styrene oxide to leave 28 g of the crude alcohol as a mixture of regioisomers which was purified by chromatography on silica, using 1:1 hexane ethylacetate, to give 16.5 g of the pure isomer, [α]23 D+56 C.
  • (R)-[1-(2-Methoxyphenyl)-4-(2-(1H-imidazol-1-yl)-2-phenylethyl)piperazine]
  • The above pure isomer (5.15 g, 0.0165m) was mixed in dichloromethane (100 ml) with triphenylphosphine (5.21 g, 0.02m) and imidazole (13 g, 0.2 m). The solution was treated over 10mins with diethylazodicarboxylate (3.8 ml) in dichloromethane (5 ml). The solution was stirred 3 days at ambient temperature and then evaporated. The residue was dissolved in ether (200 ml) and washed with water. The ether layer was then shaken with 6N HCI (3x100 ml). The combined HCI layers were shaken with ether. The HCI layer was cooled, and basified with 0.880 ammonia, and then shaken with ether. The ether extracts were washed with water and dried over magnesium sulphate, to give 6.8 g of an oil. This was dissolved in hot ethanol, acidified (EtOH-HCI), recrystallised from hot ethanol to give the title compound as the trihydrochloride monohydrate, m.p. 192-195°, [a]p+27°.
  • Example 9 1-(2-Methoxyphenyl)-4-[3-( H-imidazol-1-yl)-3-phenyl)propyl]piperazine
  • Thionyl chloride (0.88 ml) was added dropwise to an ice-cooled solution of 1-(2-methoxyphenyl)-4-(3-hydroxy-3-phenyl)piperazine (2.45 g 7.5 mmol) in dry DMF (15 ml). The solution was allowed to stand for 0.5 h and then imidazole (5.1 g, 75 mmol) added in one portion. The mixture was heated at 80°C for 1.5 h, diluted with water and extracted with ethyl acetate. The extract was dried (Na2SO4), evaporated and the residue chromatographed on silica using 5% methanol in chloroform as eluent to give the product as an oil (0.55 g). The base was dissolved in ethanol (5 ml), acidified with ethanolic-HBr and diluted with ether (3 ml) to precipitate the title compound as the trihydrobromide 0.46 g, m.p. 224-226°C.
  • Example 10 1-(2-Methoxyphenyl)-4-[2-(4-methyl-1 H-imidazol-1-yl)-2-phenyl)ethyl]piperazine
  • The title compound was prepared following the procedure of Example 2 using 4-methylimidazole instead of 2-methylimidazole. The product was converted to its trihydrochloride monohydrate, m.p. 200-205°C. (Found C, 54.5; H, 6.48; N, 11.04% C23H28N4O.3HCl. H20 requires C, 54.82; H, 6.60; N, 11.12%).
  • Example 11 5-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)-1-phenylpropyl)-3-methyl-1,2,4-oxadiazole
  • A solution of acetamidoxime (0.65 g, 8.7 mmol) in tetrahydrofuran (20 ml) added to a stirred suspension of sodium hydride (0.35 g, 60% dispersion in oil, 8.7 mmol) in tetrahydrofuran (10 ml). The reaction mixture was heated under reflux for 1 h and a solution of methyl 4-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenyl- butanoate (2.68 g, 7.3 mmol) in tetrahydrofuran (30 ml) was added dropwise. The reaction mixture was heated under reflux for a further 2 h. The cooled reaction mixture was treated with water (80 ml) and the solvent removed under reduced pressure. The aqueous residue was washed with ethyl acetate and the combined organic phases washed with water. The organic phase was dried (MgS04), concentrated and chromatographed on silica gel, eluting with ethyl acetate:hexane (2:1) to afford an oil. The oil was dissolved in acetonitrile and acidified with ethereal hydrogen chloride to give the title compound as the dihydrochloride, colourless crystals, m.p. 189.5-191.8°C.
  • Example 12 5-[2-(4-(2-Methoxyphenyl)piperazin-1-yl)-1-phenylethyl]-3-methyl-1,2,4-oxadiazole
  • A solution of acetamidoxime (0.90 g, 12.1 mmol) in tetrahydrofuran (50 ml) was added to sodium hydride (0.74 g, 60% dispersion in oil, (11.1 mmol) in tetrahydrofuran (10 ml). The reaction mixture was then heated under reflux for 1 h and a solution of methyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanote (3.58 g, 10.1 mmol) in tetrahydrofuran (50 ml) was added. The reaction mixture was heated under reflux for 0.5 h, allowed to cool and then poured into water (100 ml). The tetrahydrofuran was removed under reduced pressure and the aqueous residue washed with ethyl acetate. The combined organic phases were washed with water, dried (MgS04) and concentrated to afford a yellow oil (2.12 g). The oil was chromatographed on silica gel, eluting with ethyl acetate:hexane (1:1) to afford a pale yellow solid (1.40 g). The solid (0.50 g) was dissolved in ethyl acetate and a solution of maleic acid (0.153 g) in ethyl acetate added to afford the title compound as the maleate (0.39 g), m.p. 151.2 to 151.6°C.

Claims (17)

1. A compound of the formula
Figure imgb0016
or a pharmaceutically acceptable acid addition salt thereof, wherein
A is an alkylene chain of 1 or 2 carbon atoms optionally substituted by one or more lower alkyl groups,
R is hydrogen or lower alkyl,
R1 is an aryl or heteroaryl radical,
R2 is a mono- or bicyclic heterocyclic radical,
R3 is hydrogen, lower alkyl or hydroxy and
R4 is a aryl or heteroaryl radical.
2. A compound as claimed in claim 1 in which A is -CH2- or -CH2CH2-.
3. A compound as claimed in claim 1 or 2 in which R1 is a phenyl or naphthyl radical optionally substituted by one or more lower alkyl, lower alkoxy, halogen, halo(lower)alkyl, nitro, amino, lower(alkyl)amino, di-(lower)alkylamino, phenyl, halophenyl, (lower)alkylphenyl or (lower)alkoxyphenyl substituents.
4. A compound as claimed in any one of claims 1 to 3 in which R2 is optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, benzimidazolyl, oxadiazolyl, imidazolinyl, oxazolinyl, pyrrolidinyl, piperidinyl, morpholinyl or azepinyl.
5. A compound as claimed in claim 1 which is
1-(2-methoxyphenyl)-4-[2-1H-imidazol-1-yl)-2-(phenyl)ethyl]piperazine or
1-(2-methoxyphenyl)-4-[2-(2-methyl-[1H]imidazol-1-yl)-2-phenyl)ethyl]piperazine or
1-(2-methoxyphenyl)-4-[2-(1-pyrrolidinyl)-2-(phenyl)ethyl]piperazine or
1-(2-methoxyphenyl)-4-[2-(1H-imidazoi-2-(4-fiuorophenyi)ethyi]piperazine or
1-(2-methoxyphenyl)-4-[2-phenyl-2-(4-phenyl-1H-imidazol-1-yl)ethyl]piperazine or
1-(2-methoxyphenyl)-4-[2-(1 H-benzimadol-1- yl)-2-phenylethyl]piperazine or
(S)-[1-(2-methoxyphenyl)-4-(2-(1H-imidazol-1-yl)-2-phenylethyl)piperazine or
(R)-[1-(2-methoxyphenyl)-4-[2-(1H-imidazol-1-yl)-2-phenylethyl]piperazine or
1-(2-methoxyphenyl)-4-[3-(1H-imidazol-1-yl)-3-phenyl)propyl]piperazine or
1-(2-methoxyphenyl)-4-[2-(4-methyl-1H-imidazol-1-yl)-2-phenyl)ethyl]piperazine or
5-(3-(4-(2-methoxyphenyl)piperazin-1-yl)-1-phenylpropyl)-3-methyl-1,2,4-oxadiazole or
5-[2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-phenylethyl]-3-methyl-1,2,4-oxadiazole

or a pharmaceutically acceptable acid addition salt thereof.
6. A process for preparing a compound claimed in claim 1 which comprises
(a) alkylating a piperazine of formula
Figure imgb0017
(where R and R4 are as defined in claim 1) with an alkylating agent providing the group
Figure imgb0018
(where R1, R2, R3 and A are as defined in claim 1)
or
(b) reducing an amide of formula
Figure imgb0019
(where R, R1, R2, R3 and R4 are as defined in claim 1 and A1 is methylene optionally substituted by one or two (lower)alkyl groups
or
(c) reacting a heterocyclic compound of formula R1H or R2H (where R1 is a heteroaryl radical and R2 is as defined in claim 1) with respectively a compound of formula
Figure imgb0020
or
Figure imgb0021
(where R, R1, R2, R3, R4 and A are as defined above and Y is a leaving group) or
(d) arylating or heteroarylating a compound of formula
Figure imgb0022
or
(e) reacting a compound having the anion
Figure imgb0023
with a compound of formula
Figure imgb0024
where X is a leaving group which is activated towards nucleophilic displacement or
(f) forming an anion of a compound of formula
Figure imgb0025
(where R1, R2 and R3 are as defined in claim 1) and reacting it with a compound of formula
Figure imgb0026
(where A, R, R1, R2, R3 and R4 are as defined in claim 1 and X is a leaving group) or
(g) cyclising a compound of formula
Figure imgb0027
(where A, R, R1, R3 and R4 are as defined in claim 1 and R2' is an uncyclised group which is a precursor of a mono or bicyclic heterocyclic radical or
(h) converting a base claimed in claim 1 into a pharmaceutically acceptable acid addition salt thereof or
(i) converting a pharmaceutically acceptable acid addition salt claimed in claim 1 into a free base.
7. A pharmaceutical composition comprising a compound claimed in any one of claims 1 to 5 in association with a pharmaceutically acceptable carrier.
8. A compound as claimed in claim 1 for use as a pharmaceutical.
9. A compound as claimed in claim 1 for use as an anxiolytic, an antidepressant, a hypotensive or as an agent for regulating the sleep/wake cycle, feeding behaviour and/or sexual function.
Claims for the following Contracting States: ES, GR
1. A process for preparing a compound of the formula
Figure imgb0028
or a pharmaceutically acceptable acid addition salt thereof, wherein
A is an alkylene chain of 1 or 2 carbon atoms optionally substituted by one or more lower alkyl groups,
R is hydrogen or lower alkyl,
R1 is an aryl or heteroaryl radical,
R2 is a mono- or bicyclic heterocyclic radical,
R3 is hydrogen, lower alkyl or hydroxy and
R4 is a aryl or heteroaryl radical which process comprises
(a) alkylating a piperazine of formula
Figure imgb0029
(where R and R4 are as defined above) with an alkylating agent providing the group
Figure imgb0030
(where R1, R2, R3 and A are as defined above) or
(b) reducing an amide of formula
Figure imgb0031
(where R, R1, R2, R3 and R4 are as defined above and A1 is methylene optionally substituted by one or two (lower)alkyl groups or
(c) reacting a heterocyclic compound of formula R1H or R2H (where R1 is a heteroaryl radical and R2 is as defined in claim 1) with respectively a compound of formula
Figure imgb0032
or
Figure imgb0033
(where R, R1, R2, R3, R4 and A are as defined above and Y is a leaving group) or
(d) arylating or heteroarylating a compound of formula
Figure imgb0034
or
(e) reacting a compound having the anion
Figure imgb0035
with a compound of formula
Figure imgb0036
where X is a leaving group which is activated towards nucleophilic displacement or
(f) forming an anion of a compound of formula
Figure imgb0037
(where R1, R2 and R3 are as defined above) and reacting it with a compound of formula
Figure imgb0038
(where A, R, R1, R2, R3 and R4 are as defined above and X is a leaving group) or
(g) cyclising a compound of formula
Figure imgb0039
(where A, R, Rl, R3 and R4 are as defined above and R2' is an uncyclised group which is a precursor of a mono or bicyclic heterocyclic radical or
(h) converting a base of formula (I) into a pharmaceutically acceptable acid addition salt thereof or
(i) converting a pharmaceutically acceptable acid addition salt of the compound of formula (I) into a free base.
2. A process as claimed in claim 1 in which A is -CH2- or -CH2CH2-.
3. A process as claimed in claim 1 or 2 in which R1 is a phenyl or naphthyl radical optionally substituted by one or more lower alkyl, lower alkoxy, halogen, halo(lower)alkyl, nitro, amino, lower(alkyl)amino, di(lower- )alkylamino, phenyl, halophenyl, (lower)alkylphenyl or (lower)alkoxyphenyl substituents.
4. A process as claimed in any one of claims 1 to 3 in which R2 is optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, benzimidazolyl, oxadiazolyl, imidazolinyl, oxazolinyl, pyrrolidinyl, piperidinyl, morpholinyl or azepinyl.
5. A process as claimed in claim 1 in which the product is
1-(2-methoxyphenyl)-4-[2-1H-imidazol-1-yl)-2-(phenyl)ethyl]piperazine or
1-(2-methoxyphenyl)-4-[2-(2-methyl-[1H]imidazol-1-yl)-2-phenyl)ethyl]piperazine or
1-(2-methoxyphenyl)-4-[2-(1-pyrrolidinyl)-2-(phenyl)ethyl]piperazine or
1-(2-methoxyphenyl)-4-[2-(1H-imidazoi-2-(4-fiuorophenyi)ethyi]piperazine or
1-(2-methoxyphenyl)-4-[2-phenyl-2-(4-phenyl-1H-imidazol-1-yl)ethyl]piperazine or
1-(2-methoxyphenyl)-4-[2-(1H-benzimadol-1-yl)-2-phenylethyl]piperazine or
(S)-[1-(2-methoxyphenyl)-4-(2-(1H-imidazol-1-yl)-2-phenylethyl)piperazine or
(R)-[1-(2-methoxyphenyl)-4-[2-(1H-imidazol-1-yl)-2-phenylethyl]piperazine or
1-(2-methoxyphenyl)-4-[3-(1H-imidazol-1-yl)-3-phenyl)propyl]piperazine or
1-(2-methoxyphenyl)-4-[2-(4-methyl-1H-imidazol-1-yl)-2-phenyl)ethyl]piperazine or
5-(3-(4-(2-methoxyphenyl)piperazin-1-yl)-1-phenylpropyl)-3-methyl-1,2,4-oxadiazole or
5-[2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-phenylethyl]-3-methyl-1,2,4-oxadiazole

or a pharmaceutically acceptable acid addition salt thereof.
6. A process for preparing a pharmaceutical composition which comprises bringing a compound of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier.
7. A process as claimed in claim 6 wherein the active ingredient is prepared by a process claimed in claim 1.
EP91308969A 1990-10-03 1991-10-01 Piperazine derivatives Expired - Lifetime EP0479546B1 (en)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2692894A1 (en) * 1992-06-24 1993-12-31 Irceba Aryl-1- (o-alkoxy-phenyl-4-piperazinyl-1) -2,3-or 4-alkanols, process for their preparation and their use in the preparation of medicaments.
WO1995002592A1 (en) * 1993-07-16 1995-01-26 John Wyeth & Brother Ltd. N-(piperidinyl-1-alkyl)-substituted cyclohexane carboxylic acid amides as 5-ht1a receptor antagonists
DE19801597A1 (en) * 1998-01-17 1999-07-29 Aventis Res & Tech Gmbh & Co 1-Aryl-4-arylethyl-piperazine derivative preparation in high yield from aryl-piperazine and aryl olefin, used as drug intermediate
WO2002000259A1 (en) * 2000-06-27 2002-01-03 Taisho Pharmaceutical Co., Ltd. Remedial agent for anxiety neurosis or depression and piperazine derivative
WO2003053927A1 (en) * 2001-12-21 2003-07-03 Taisho Pharmaceutical Co.,Ltd. Piperazine derivative
WO2003105853A1 (en) * 2002-06-12 2003-12-24 Chemocentryx, Inc. 1-aryl-4-substituted piperazines derivatives for use as ccr1 antagonists for the treatment of inflammation and immune disorders
US6894052B1 (en) 1997-08-01 2005-05-17 Recordati S.A. Chemical And Pharmaceutical Company Diarylalkylpiperazines active on the lower urinary tract
EP1691810A1 (en) * 2003-12-09 2006-08-23 ChemoCentryx Inc Substituted piperazines
US7435831B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7435830B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7589199B2 (en) 2002-06-12 2009-09-15 Chemocentryx, Inc. Substituted piperazines
US7842693B2 (en) 2002-06-12 2010-11-30 Chemocentryx, Inc. Substituted piperazines

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9021535D0 (en) * 1990-10-03 1990-11-14 Wyeth John & Brother Ltd Piperazine derivatives
US5633377A (en) * 1990-12-28 1997-05-27 Neurogen Corporation 4-piperidino- and piperazinomethyl-2-cyclohexyl imidazole derivatives; dopamine receptor subtype specific ligands
US5681956A (en) * 1990-12-28 1997-10-28 Neurogen Corporation 4-aryl substituted piperazinylmethyl phenylimidazole derivatives; a new class of dopamine receptor subtype specific ligands
US5219856A (en) * 1992-04-06 1993-06-15 E. I. Du Pont De Nemours And Company Angiotensin-II receptor blocking, heterocycle substituted imidazoles
SE9202265D0 (en) * 1992-07-31 1992-07-31 Kabi Pharmacia Ab NOVEL- PYRIDYL AND PYRIMIDYLPIPERAZINE DERIVATIVES
US5314885A (en) * 1992-09-11 1994-05-24 Mcneilab, Inc. Cyclic benzylamino, benzylamido, and benzylimido antipsychotic agents
US5609849A (en) * 1994-03-11 1997-03-11 The Trustees Of The University Of Pennsylvania Serotonin (5-HT1A) receptor ligands and imaging agents
US6166205A (en) * 1998-09-02 2000-12-26 Neurogen Corporation 2-Aryl-4-(1-[4-heteroaryl]piperazin-1-yl)methylimidazoles: dopamine . D.sub4 receptor subtype ligands
KR100347672B1 (en) * 2000-05-15 2002-08-07 중앙섬유기계 주식회사 Links-links jacquard forming circular knitting machine with computer
CN102241664B (en) * 2010-05-13 2014-11-12 上海医药工业研究院 Aralkyl diamine derivatives and use thereof as antidepressants

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3900495A (en) * 1971-05-27 1975-08-19 American Cyanamid Co Intermediate indolines
US4060526A (en) * 1967-12-20 1977-11-29 Pennwalt Corporation 1-Heterocyclic alkyl-1,2,3,4-tetrahydroquinazolinones and analgesic intermediates thereof
US4122176A (en) * 1974-07-01 1978-10-24 Sumitomo Chemical Company, Limited 3-(Piperazinoalkyl)-benz-2,1-isoxazoles
EP0241053A1 (en) * 1986-02-27 1987-10-14 Duphar International Research B.V Aryl-substituted (N-piperidinyl)-methyl- and (N-piperazinyl) methylazoles having antipsychotic properties
EP0395312A2 (en) * 1989-04-22 1990-10-31 JOHN WYETH & BROTHER LIMITED Piperazine derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1597591A (en) * 1977-01-12 1981-09-09 Degussa Dithienyl alkylamines and alkenylamines and a process for their production
US4732895A (en) * 1986-05-02 1988-03-22 American Cyanamid Company α-[5-methyl-2-(pyridinyl)-1H-imidazol-4-yl]substituted-1-piperazineethanols useful for treating hypertension

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4060526A (en) * 1967-12-20 1977-11-29 Pennwalt Corporation 1-Heterocyclic alkyl-1,2,3,4-tetrahydroquinazolinones and analgesic intermediates thereof
US3900495A (en) * 1971-05-27 1975-08-19 American Cyanamid Co Intermediate indolines
US4122176A (en) * 1974-07-01 1978-10-24 Sumitomo Chemical Company, Limited 3-(Piperazinoalkyl)-benz-2,1-isoxazoles
EP0241053A1 (en) * 1986-02-27 1987-10-14 Duphar International Research B.V Aryl-substituted (N-piperidinyl)-methyl- and (N-piperazinyl) methylazoles having antipsychotic properties
EP0395312A2 (en) * 1989-04-22 1990-10-31 JOHN WYETH & BROTHER LIMITED Piperazine derivatives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
INDIAN JOURNAL OF CHEMISTRY Section B, vol. 14B, no. 9, September 1976, pages 714-716; K.M.R. PLILAI et al.: "Agents Acting on the Central Nervous System: Part XXVI - Synthesis of Some Diphenylpropylamine & Dibenzocycloheptenylethylamine Derivatives" *
JOURNAL OF MEDICINAL CHEMISTRY vol. 11, no. 6, November 1968, pages 1144-1150; R.N. PRASAD et al.: "Potential Antihypertensive Agents. II. Unsymmetrically 1,4-Disubstituted Piperazines " *
JOURNAL OF MEDICINAL CHEMISTRY vol. 12, no. 5, September 1969, pages 860-865; C.V. DELIWALA et al.: "Synthesis and Central Nervous System Depressant Activity of New Piperazine Derivatives and Related Compounds" *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994000442A1 (en) * 1992-06-24 1994-01-06 Institut De Recherches Chimiques Et Biologiques Appliquees (I.R.C.E.B.A.) 1-aryl(4-o-alkoxyphenyl 1-piperazinyl)-2, -3 or -4 alkanols, process for their preparation and use thereof in the preparation of drugs
FR2692894A1 (en) * 1992-06-24 1993-12-31 Irceba Aryl-1- (o-alkoxy-phenyl-4-piperazinyl-1) -2,3-or 4-alkanols, process for their preparation and their use in the preparation of medicaments.
WO1995002592A1 (en) * 1993-07-16 1995-01-26 John Wyeth & Brother Ltd. N-(piperidinyl-1-alkyl)-substituted cyclohexane carboxylic acid amides as 5-ht1a receptor antagonists
US5763460A (en) * 1993-07-16 1998-06-09 John Wyeth & Brother Limited N-(piperidinyl-1-alkyl)-substituted cyclohexane carboxylic acid amides as 5-htia receptor antagonists
US6894052B1 (en) 1997-08-01 2005-05-17 Recordati S.A. Chemical And Pharmaceutical Company Diarylalkylpiperazines active on the lower urinary tract
DE19801597A1 (en) * 1998-01-17 1999-07-29 Aventis Res & Tech Gmbh & Co 1-Aryl-4-arylethyl-piperazine derivative preparation in high yield from aryl-piperazine and aryl olefin, used as drug intermediate
DE19801597C2 (en) * 1998-01-17 2001-05-03 Aventis Res & Tech Gmbh & Co Base-catalyzed synthesis of 1-aryl-4- (arylethyl) piperazines from aromatic olefins and 1-arylpiperazines
US6949552B2 (en) 2000-06-27 2005-09-27 Taisho Pharmaceutical Co., Ltd. Remedial agent for anxiety neurosis or depression and piperazine derivative
WO2002000259A1 (en) * 2000-06-27 2002-01-03 Taisho Pharmaceutical Co., Ltd. Remedial agent for anxiety neurosis or depression and piperazine derivative
WO2003053927A1 (en) * 2001-12-21 2003-07-03 Taisho Pharmaceutical Co.,Ltd. Piperazine derivative
AU2003236500B9 (en) * 2002-06-12 2009-07-02 Chemocentryx, Inc. 1-aryl-4-substituted piperazine derivatives for use as CCR1 antagonists for the treatment of inflammation and immune disorders
US8324216B2 (en) 2002-06-12 2012-12-04 Chemocentryx, Inc. Substituted piperazines
US7157464B2 (en) 2002-06-12 2007-01-02 Chemocentryx, Inc. Substituted piperazines
US7842693B2 (en) 2002-06-12 2010-11-30 Chemocentryx, Inc. Substituted piperazines
US7589199B2 (en) 2002-06-12 2009-09-15 Chemocentryx, Inc. Substituted piperazines
US7449576B1 (en) 2002-06-12 2008-11-11 Chemocentryx, Inc. Substituted piperazines
AU2003236500B2 (en) * 2002-06-12 2009-01-08 Chemocentryx, Inc. 1-aryl-4-substituted piperazine derivatives for use as CCR1 antagonists for the treatment of inflammation and immune disorders
WO2003105853A1 (en) * 2002-06-12 2003-12-24 Chemocentryx, Inc. 1-aryl-4-substituted piperazines derivatives for use as ccr1 antagonists for the treatment of inflammation and immune disorders
EP1691810A4 (en) * 2003-12-09 2009-07-01 Chemocentryx Inc Substituted piperazines
EP1691810A1 (en) * 2003-12-09 2006-08-23 ChemoCentryx Inc Substituted piperazines
US7435830B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7435831B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles

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